title: The safety profile of a cationic lipid-mediated cystic fibrosis gene transfer agent following repeated monthly aerosol administration to sheep.
abstract: Clinically effective gene therapy for Cystic Fibrosis has been a goal for over 20 years. A plasmid vector (pGM169) that generates persistent expression and reduced host inflammatory responses in mice has raised prospects for translation to the clinic. The UK CF Gene Therapy Consortium is currently evaluating long-term repeated delivery of pGM169 complexed with the cationic lipid GL67A in a large Multidose Trial. This regulatory-compliant evaluation of aerosol administration of nine doses of pGM169/GL67A at monthly intervals, to the sheep lung, was performed in preparation for the Multidose Trial. All sheep tolerated treatment well with no adverse effects on haematology, serum chemistry, lung function or histopathology. Acute responses were observed in relation to bronchoalveolar cellularity comprising increased neutrophils and macrophage numbers 1 day post-delivery but these increases were transient and returned to baseline. Importantly there was no cumulative inflammatory effect or lung remodelling with successive doses. Molecular analysis confirmed delivery of pGM169 DNA to the airways and pGM169-specific mRNA was detected in bronchial brushing samples at day 1 following doses 1, 5 and 9. In conclusion, nine doses of pGM169/GL67A were well tolerated with no significant evidence of toxicity that would preclude adoption of a similar strategy in CF patients.
authors.affiliation: Department of Gene Therapy, Imperial College London, Manresa Road, London SW3 6LR, UK.
authors.forename: Eric W F W
authors.initials: EW
authors.lastname: Alton
authors.forename: Alison
authors.initials: A
authors.lastname: Baker
authors.forename: Eilidh
authors.initials: E
authors.lastname: Baker
authors.forename: A Christopher
authors.initials: AC
authors.lastname: Boyd
authors.forename: Seng H
authors.initials: SH
authors.lastname: Cheng
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Coles
authors.forename: D David S
authors.initials: DD
authors.lastname: Collie
authors.forename: Heather
authors.initials: H
authors.lastname: Davidson
authors.forename: Jane C
authors.initials: JC
authors.lastname: Davies
authors.forename: Deborah R
authors.initials: DR
authors.lastname: Gill
authors.forename: Catherine
authors.initials: C
authors.lastname: Gordon
authors.forename: Uta
authors.initials: U
authors.lastname: Griesenbach
authors.forename: Tracy
authors.initials: T
authors.lastname: Higgins
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Hyde
authors.forename: J Alastair
authors.initials: JA
authors.lastname: Innes
authors.forename: Dominique
authors.initials: D
authors.lastname: McCormick
authors.forename: Michael
authors.initials: M
authors.lastname: McGovern
authors.forename: Gerry
authors.initials: G
authors.lastname: McLachlan
authors.forename: David J
authors.initials: DJ
authors.lastname: Porteous
authors.forename: Ian
authors.initials: I
authors.lastname: Pringle
authors.forename: Ronald K
authors.initials: RK
authors.lastname: Scheule
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Shaw
authors.forename: Sionagh
authors.initials: S
authors.lastname: Smith
authors.forename: Stephanie G
authors.initials: SG
authors.lastname: Sumner-Jones
authors.forename: Peter
authors.initials: P
authors.lastname: Tennant
authors.forename: Christina
authors.initials: C
authors.lastname: Vrettou
mesh_terms: D000336:Aerosols; D000818:Animals; D003550:Cystic Fibrosis / Q000235:genetics*; D004848:Epithelium / Q000378:metabolism; D005260:Female; D018014:Gene Transfer Techniques; D008055:Lipids / Q000737:chemistry*; D008168:Lung / Q000378:metabolism*; D008297:Male; D012756:Sheep
chemical_list: D000336:Aerosols; D008055:Lipids
keywords: Epithelium; Gene transfer; Lipid; Lung